The overall goal of this proposal is to advance a new and powerful paradigm in pulmonary physiology; one we call Image-Functional Modeling (IFM). Conceptually, IFM synthesizes imaging data and mechanical and ventilation function data taken in the same subject with anatomically specific three-dimensional models of the lung. Boston University, as the lead institution will partner with the Massachusetts General Hospital, Brigham and Women's Hospital, Tufts University School of Veterinary Medicine, and the University of Aukland to exploit IFM via the following imaging modalities: Positive Emission Tomography (PET), High Resolution Computer Tomography (HRCT), and Hyperpolarized Helium Magnetic Resonance Imaging (Hyp 3/He MRI). The IFM will be applied to asthma and to respiratory distress syndrome (RDS). Our specific aims are to: . Advance a 3D anatomically specific computational model of the lung that can predict overall and dynamic lung mechanical and ventilation function while permitting the imposition of a heterogeneous insult to explicit anatomic locations. This model will consist of a scaffold of modules across multiple biological scales resulting in an open source simulation resource for the general respiratory structure-function community. . Synthesize our computational models with imaging and mechanical functional data taken simultaneously in the same subjects. The imaging data will quantify ventilation distribution and/or airway geometry while the mechanical function data will include standard clinical lung function indices (eg., spirometry) and dynamic lung function. Applications of IFM to asthma and RDS will quantify the likelihood of two hypotheses: a) The primary cause of functional degradation in both ventilation and mechanics during asthma lies within the smafl airways (d<2mm), namely, their constriction pattern; and b) During mechanical ventilation, setting the level of positive end-expiratory pressure to reduce dynamic heterogeneity will minimize risk of lung injury' while optimizing ventilation distribution. . Perform a rigorous sensitivity analysis to a) examine the impact of local and distributed disease induced changes in geometry and the biomaterial properties on function; and b) predict the likely impact and outcome of specific clinical interventions or therapies on total and local lung function. The IFM paradigm represents a breakthrough in quantitative image interpretation and in model based understanding of lung function. Comprehensive and integrative new hypotheses and insights into lung pathophysiology and in medical practice will evolve in ways unachievable by considering any of these domains alone. The long term goal is to provide guidance on interventions such as pharmaceutics and mechanical ventilation, and to do so on a personalized basis.